The major goal of this research project is to further examine involvement of ocular autonomic input in the mediation of the intraocular pressure lowering effects of marihuana extract and natural and synthetic cannabinoids. Dose-response curves for reduction of ocular tension after administration of marihuana extract, delta-9-tetrahydrocannabinol (Delta9-THC), cannabidiol, cannabinol, cannabichromene, cannabicyclol, cannabigerol, and three synthetic nitrogen-containing cannabinoids: Pfizer CP-44, 001 (nantradol), Abbott 43981, and Abbott 42574 will first be determined in rabbits, cats and cynomolgus monkeys. Structure-activity relationships will be elucidated on the basis of the results. Rate of trolerance development to the pressure lowering effects after chronic administration will be examined. Ocular and CNS toxicity after both acute and chronic cannabinoid treatment will be determined. Effects of selective alteration of ocular adrenergic or cholinergic input on responsiveness to these cannabinoids will then be examined. Interactions between these cannabinoids and autonomic drugs will also be determined after both acute and chronic cannabinoid administration. The changes in aqueous humor formation rate and/or outflow facility contributing to observed changes in effectiveness will then be assessed. Possible roles of cyclic AMP and the high affinity choline uptake system in the mediation of the pressure lowering effect of cannabinoids will finally be explored with the use of biochemical techniques.